Organic synthesis reactions on-water at the organic-liquid water interface.

Organic reactions that occur at the water interface for water-insoluble compounds, and reactions in water solution for water soluble compounds, has added a powerful dimension to prospects for organic synthesis under more beneficial economic and environmental conditions. Many organic molecules are partially soluble in water and reactions that appear as heterogeneous mixtures and suspensions may involve on-water and in-water reaction modes occurring simultaneously. The behavior of water molecules and organic molecules at this interface is discussed in the light of reported theoretical and experimental studies. The on-water catalytic effect, relative to neat reactions or organic solvents, ranges from factors of several hundred times to 1-2 times and it depends on the properties of reactant compounds. In some cases when on-water reactions produce quantitative yields of water-insoluble products they can reach ideal synthetic aspirations.

Understanding "on-water" catalysis of organic reactions. Effects of H+ and Li+ ions in the aqueous phase and nonreacting competitor H-bond acceptors in the organic phase: on H2O versus on D2O for Huisgen cycloadditions.

For a typical Huisgen cycloaddition, carried out on water, the behavior of water molecules at the oil-water interface depended on the properties of the reactants. With weakly basic reactants, a small quantity of added H(+) (HClO4, 0.0001-0.01 M) present in the aqueous phase had negligible effects, but larger quantities of H(+) (HClO4, 0.1-3.0 M) increased the catalytic effect and caused protons to cross the water-organic interface and affect the products. Added Li(+) ions (LiClO4, 0.1-3.0 M) had no effect for on-water reactions but enhanced the rates and endo products for in-water reactions. For these cycloaddition reactions, the product endo:exo ratios, when compared to those in organic solvents, can be used to distinguish between the on-water and in-water modes. Comparisons of organic reactions on H2O and on D2O indicate that on-water catalysis ranges from weak to strong trans-phase H-bonding for reactants with basic pK(a) < ca. -6 and to interfacial proton transfer for reactants with higher basic pK(a) > ca. 2 (pKa of conjugate acid). Water shows a chameleon-type response to organic molecules at hydrophobic surfaces.

Water and organic synthesis: a focus on the in-water and on-water border. Reversal of the in-water Breslow hydrophobic enhancement of the normal endo-effect on crossing to on-water conditions for Huisgen cycloadditions with increasingly insoluble organic liquid and solid 2π-dipolarophiles.

Measurements of the endo/exo product ratios for Huisgen cycloadditions with a series of vinyl ketones, alkyl acrylates, and substituted styrenes as dipolarophiles with phthalazinium and pyridazinium dicyanomethanide 1,3-dipoles in acetonitrile and water show that as the reactions change from in-water (large hydrophobic enhancement of endo-products) to on-water, the hydrophobic enhancement of the endo-products is reduced and partially reversed (relative to acetonitrile). An expected increase of the endo-effect with increasing hydrophobic character of the dipolarophile is overcome by decreasing water solubility causing changeover to on-water conditions. On-water reactions do not show increased cycloaddition endo-effects (relative to organic solvents) as do in-water reactions.

Computational investigation of rearrangements in huisgen cycloadducts of azolium N-dicyanomethanide 1,3-dipoles with alkynes: a mechanistic panoply.

The reaction surfaces leading to rearrangements and ring expansions of azapentalene cycloadducts of imidazolo- and triazolodicyanomethanide 1,3-dipoles with alkynes are studied with the B3LYP DFT method using the 6-31G(d) and 6-311+G(2d,p) basis sets. The surprisingly complex surface involves (1) consecutive but not combined pericyclic steps, a coarctate TS, and pseudopericyclic mechanisms, (2) anchimerically assisted H-atom transfer competing effectively with concerted symmetry-allowed sigmatropic steps, and (3) azolium methanide zwitterions and ketenimines as key intermediates. The azolium methanide is identified as the intermediate detected previously in a variable-temperature NMR experiment that converted the unstable cycloadduct to product imine.

A ceric ammonium nitrate N-dearylation of N-p-anisylazoles applied to pyrazole, triazole, tetrazole, and pentazole rings: release of parent azoles. generation of unstable pentazole, HN5/N5-, in solution.

The reaction of cerium(IV) ammonium nitrate (CAN) with a range of N-(p-anisyl)azoles in acetonitrile or methanol solvents leads to N-dearylation releasing the parent NH-azole and p-benzoquinone in comparable yields. The scope and limitations of the reaction are explored. It was successful with 1-(p-anisyl)pyrazoles, 2-(p-anisyl)-1,2,3-triazoles, 2-(p-anisyl)-2H-tetrazoles, and 1-(p-anisyl)pentazole. The dearylation renders the p-anisyl group as a potentially useful N-protecting group in azole chemistry. The azole released in solution from 1-(p-anisyl)pentazole is unstable HN5, the long-sought parent pentazolic acid. p-Anisylpentazole samples were synthesized with combinations of one, two, and three 15N atoms at all positions of the pentazole ring. The unstable HN5/N5- produced at -40 degrees C did not build up in the solution but degraded to azide ion and nitrogen gas with a short lifetime. The 15N-labeling of the N3- ion obtained from all samples proved unequivocally that it came from the degradation of HN5 (tautomeric forms) and/or its anion N5- in the solution.

One-pot synthesis of fluorescent 2,5-dihydro-1,2,3-triazine derivatives from a cascade rearrangement sequence in the reactions of 1,2,3-triazolium-1-aminide 1,3-dipoles with propiolate esters.

The reactions of 1,2,3-triazolium-1-aminides 1 (readily available from benzil bishydrazones) with propiolate esters leads to fluorescent 2,5-dihydro-1,2,3-triazine derivatives 2, 3 in one pot. These synthetic reactions can be carried out in acetone, in water, or under solvent-free conditions. The reactions involve a Huisgen cycloaddition followed by a sequence of rearrangements. The final ring-expansion step was blocked by linking a six-methylene hydrocarbon chain between the prospective 1,2,3-triazine C-4 and C-6 atoms, using substrate 8 which gave the fused tricyclic azapropellane product 9 exclusively. X-ray crystal structures were determined for two 2,5-dihydro-1,2,3-triazine derivatives and for compound 9. The UV absorption of the 1,2,3-triazine derivatives showed a dual absorption at ca. 310 and ca. 390 nm with fluorescent emission at ca. 480 and 528 nm (for excitation at 317 nm). The significant Stokes shift of ca. 200 nm shows the potential for biological fluorescent labeling experiments.

The influence of water on the rates of 1,3-dipolar cycloaddition reactions: trigger points for exponential rate increases in water-organic solvent mixtures. Water-super versus water-normal dipolarophiles.

The nature of the rate enhancements caused by gradually increasing the mole fraction of water in the solvent (from 0 to 1) for the cycloaddition reactions of pyridazinium-dicyanomethanide 1,3-dipole, 2, with the dipolarophiles ethyl vinyl ketone (a water-super dipolarophile) and methyl acrylate (a water-normal dipolarophile) in the organic solvents acetonitrile, acetone, methanol, ethanol, and tert-butyl alcohol at 37 degrees C are explored. In each case as the mole fraction of water surpassed ca. 0.9, exponential rate enhancements were triggered. When methanol replaced water, the rate enhancements were smaller, and no triggering effect was observed. The dramatic rate enhancement triggered for the water-super dipolarophile was significantly reduced as the temperature was raised in the range 29-64 degrees C. The results suggest that a dominant hydrogen-bonding effect operates in water-induced rate enhancements of 1,3-dipolar cycloaddition reactions with water-super dipolarophiles as well as the hydrophobic effect. The hydrogen-bonding effect involves secondary bridging hydrogen bonding from the primary water-solvation shell of the transition state and the growth of structured water clusters. Theoretical calculations strongly support these conclusions.